Study of Co-trimoxazole and Proton Pump Inhibition Using Pragmatic Design in Idiopathic Pulmonary Fibrosis - CleanUP-IPF

 描述(由申请人提供)：特发性肺纤维化是一种间质性肺纤维化，其特征是确诊后中位生存期为3-5年，但表现为不均匀的纵向疾病进展。新药的最新研究证实了对用力肺活量纵向变化的有益影响，但对临床终点或健康状况的益处并不一致。这两种药物都很难容忍，而且可能会贵得令人望而却步。进行临床试验以评估临床终点需要大量的患者入选，并进行充分的时间跟踪。无法迅速招募足够数量的IPF患者意味着许多关键的临床问题尚未得到解决。严格的纳入标准确保患者登记参加临床试验 通常与临床实践中看到的不同。仍然迫切需要使用创新的、 务实的研究旨在确定耐受性良好且价格低廉的治疗方法，以改善IPF患者的临床结果。我们小组是第一个发现肺微生物群落异常与IPF患者疾病进展独立相关的研究小组。额外的初步数据将其与改变的宿主反应的循环基因表达特征联系在一起。有趣的是，一个研究小组建议，与匹配的安慰剂相比，接受甲氧苄啶/磺胺甲恶唑治疗的IPF患者的临床结果有所改善。所有这些数据表明，肺部微生物群异常与宿主反应的遗传易感性相互作用，可能与IPF的临床结局受损有关。我们的主要假设是，IPF患者的抗菌治疗将改善临床结果。我们的长期目标是定义IPF中针对患者的治疗方法。使用务实的试验设计清理-IPF将消除临床试验登记的许多已知障碍，以便招募具有高度临床实践代表性的患者群体。我们预计将证明：1)在IPF中进行一项大规模、务实的研究是可行的，并将确定FVC以外的具有临床意义的终点；2)抗微生物治疗将改善临床结果；以及3)遗传倾向的患者将对治疗产生不同的反应。清理-IPF将彻底改变IPF的未来研究，并提供将改变治疗指南的数据。

 DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis a fibrotic interstitial lung disease characterized by a median survival of 3-5 years post-diagnosis but exhibits heterogeneous longitudinal disease progression. Recent studies of novel agents confirm beneficial effects on longitudinal change in forced vital capacity but inconsistent benefits on clinical endpoints or health status. Both agents are difficult to tolerate and are likely to be prohibitively expensive. Conducting clinical trials to assess clinical endpoints requires that larg numbers of patients are enrolled and followed for a sufficient period of time. The inability to rapidly recruit sufficient numbers of IPF patients means that many key clinical questions have not been addressed. Restrictive inclusion criteria ensure that patients enrolled in clinical trials often differ from those seen in clinical practice. There remains a critical need to use innovative, pragmatic study designs to identify well tolerated and inexpensive therapies which improve clinical outcomes in patients with IPF. Our group was the first to identify that an abnormal lung microbial community is independently associated with disease progression in IPF subjects. Additional preliminary data link this to a circulating gene expression signature of altered host response. Intriguingly, one investigative group has suggested improved clinical outcomes in IPF patients treated with trimethoprim/ sulfamethoxazole compared to a matched placebo. The totality of these data suggests that an abnormal lung microbiome interacting with genetic susceptibility in host response may be associated with impaired clinical outcomes in IPF. Our principal hypothesis is that antimicrobial therapy in IPF patients will improve clinical outcomes. Our long-term goal is to define patient-specific therapy in IPF. Using a pragmatic trial design CleanUP-IPF will remove many of the known obstacles to clinical trial enrollment in order to recruit a patient population that is highly representative of those seen in clinical practice. We anticipate demonstrating that: 1) a large, pragmatic study in IPF is feasible and will identify clinically meaningful endpoints beyond FVC; 2) anti- microbial therapy will improve clinical outcomes; and 3) genetically predisposed patients will experience differential response to therapy. CleanUP-IPF will revolutionize future studies in IPF and provide data that will alter therapeutic guidelines.